Nuclear distribution of claudin-2 increases cell proliferation in human lung adenocarcinoma cells |
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Authors: | Akira Ikari Ryo Watanabe Tomonari Sato Saeko Taga Shun Shimobaba Masahiko Yamaguchi Yasuhiro Yamazaki Satoshi Endo Toshiyuki Matsunaga Junko Sugatani |
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Affiliation: | 1. Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan;2. School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan |
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Abstract: | Claudin-2 is expressed in human lung adenocarcinoma tissue and cell lines, although it is absent in normal lung tissue. However, the role of claudin-2 in cell proliferation and the regulatory mechanism of intracellular distribution remain undefined. Proliferation of human adenocarcinoma A549 cells was decreased by claudin-2 knockdown together with a decrease in the percentage of S phase cells. This knockdown decreased the expression levels of ZONAB and cell cycle regulators. Claudin-2 was distributed in the nucleus in human adenocarcinoma tissues and proliferating A549 cells. The nuclear distribution of ZONAB and percentage of S phase cells were higher in cells exogenously expressing claudin-2 with a nuclear localization signal than in cells expressing claudin-2 with a nuclear export signal. Nuclear claudin-2 formed a complex with ZO-1, ZONAB, and cyclin D1. Nuclear distribution of S208A mutant, a dephosphorylated form of claudin-2, was higher than that of wild type. We suggest that nuclear distribution of claudin-2 is up-regulated by dephosphorylation and claudin-2 serves to retain ZONAB and cyclin D1 in the nucleus, resulting in the enhancement of cell proliferation in lung adenocarcinoma cells. |
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Keywords: | ZONAB, ZO-1 associated nucleic acid binding protein NSCLC, non-small cell lung cancer TJs, tight junctions |
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